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Obesity and Pre-diabetes in Pediatrics

Obesity and Pre-diabetes in Pediatrics. David Olson, MD PhD Assistant Professor of Pediatrics University of Michigan Medical School MAPA Fall CME Conference October 11, 2013. Address the link between obesity, insulin resistance and the development of diabetes

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Obesity and Pre-diabetes in Pediatrics

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  1. Obesity and Pre-diabetes in Pediatrics David Olson, MD PhD Assistant Professor of Pediatrics University of Michigan Medical School MAPA Fall CME ConferenceOctober 11, 2013

  2. Address the link between obesity, insulin resistance and the development of diabetes • Review the pathophysiology of Insulin resistance and T2DM • Review the diagnostic criteria for diabetes • Explore the treatment options for insulin resistance, pre-diabetes and diabetes in children

  3. Case Presentation • HPI: 12 year 6 month old Latino male with a concern about increasing weight gain. He is in good health. • PMH: Entirely healthy Meds: none • FH: Parents: Father 5’10”, Mother 5’2”: Type 2 DM, HTN, obesity • ROS: negative for polyuria, polydipsia • Physical Exam: Ht 62”, Wt 189.2 lb (85.8 kg), P 90, BP 118/67 BMI 34.6 kg/m2 (>99%ile) • Diffuse adiposity • Skin: acanthosisnigricanson the neck and in the axillae • No thyromegaly • Chest clear, no murmur • Abdominal exam: unreliable • Tanner 3 genitalia

  4. AcanthosisNigricans

  5. Body Mass Index (BMI=kg/m2) Categories Category Former TerminologyRecommended <5th % Underweight Underweight 5-84th % Healthy weight Healthy weight 85-94th % At risk of overweight Overweight >95th % Overweight Obese PEDIATRICSVolume 120, Supplement 4, December 2007, p. S167.

  6. Trends in US Childhood Obesity • Since 1980, obesity prevalence has nearly tripled to 16.9%, with no difference between 2007-2008 and 2009-2010 for ages 2-19. • Racial and ethnic disparities in obesity prevalence: increased in African Americans, Hispanics, American Indians/Alaska Natives. • The prevalence of extreme obesity among low income preschoolers: • From 2003 through 2010, decreased slightly from 2.22% to 2.07% • From 1998 through 2003, increased from 1.75% to 2.22% • The prevalence of obesity among low income preschoolers: • From 2003 through 2010, decreased slightly from 15.21% to 14.94% • From 1998 through 2003, increased from 13.05% to 15.21% Sources: cdc.gov/obesity/childhood/index.html Ogden et al. JAMA 301(5): 483

  7. Prevalence of obesity across racial groups (2009-2010) Children (Age 6-11)Adolescents (Age 12-19) % Prevalence % Prevalence RaceOverwtObeseOverwtObese Black (Non-Hispanic) 42.7 28.6 41.2 23.7 Mexican American 39.0 22.1 43.4 23.9 White (Non-Hispanic) 27.6 13.9 30.0 16.1 Source: Ogden et. al. JAMA. 2012;307:483-490.

  8. Co-morbidities associated with Obesity • Stroke • Hypertension • Vascular disease • Hypertension • Asthma • Cancer • Gestational Diabetes • Fetal Programming • Orthopedic/Arthritis • Depression • Insulin Resistance • Hyperlipidemia • Prediabetes • Type 2 Diabetes • NAFLD

  9. National Diabetes Statistics, 2011 http://diabetes.niddk.nih.gov/dm/pubs/statistics

  10. Predicted Burden of Prediabetes and Diabetes Cheng, et.al Nat. Review Endocrinol. 8:228-236 (2012)

  11. Important Definitions • Pre-diabetes • Impaired fasting glucose IFG) of 100-125 mg/dl, OR • Impaired glucose tolerance (IGT), with plasma glucose of 140-199 mg/dl 2 hours after a standard OGTT (75 grams of glucola) • Diabetes (in asymptomatic patients) • Fasting venous plasma sugar > 126 mg/dl or, • OralGTT with BG> 200 mg/dL at 2hr (**must be repeated) • Metabolic syndrome • Combination of abnormalities predisposing individuals to diabetes and cardiovascular disease. • Pediatric definitions are debated, incidence increasing • Insulin resistance is the principal metabolic abnormality

  12. What is the Metabolic Syndrome? At least 3 of 5 following criteria: • Abdominal obesity (> 90th percentile waist circumference) • Elevated blood pressure (>90th percentile) • Fasting glucose > or = 110 mg/dl • Fasting triglycerides >/= 110 mg/dl • HDL Cholesterol </= 40 mg/dl Prevalence estimate: over 2 million American adolescents Duncan et al, Diabetes Care 27: 2438-2443

  13. Links Between Obesity and Insulin Resistance • Hyperinsulinemia is critical, risk factors include: • Genetically at-risk children • Simple carbohydrates in the diet • Inactivity • Obesity • Leads to reduction in fatty acid oxidation and hypertriglyceridemia • Triglycerides accumulate in liver and muscle->decreased glucose uptake.

  14. The Path from Insulin Resistance to Pre-diabetes to Type 2 Diabetes • Insulin Resistance, normal glucose tolerance 2) Insulin Resistance, increased post-prandial glucose (PPG), decreased first phase insulin release, abnormal GTT(IGT-“pre-diabetes”) 3) Insulin Resistance, Increased fasting (IFG) and PPG (IFG=“pre-diabetes”) 4) Diabetes, Insulin Resistance (IR) “Most people with pre-diabetes develop type 2 diabetes within 10 years, unless they lose 5 to 7 percent of their body weight making changes in their diet and level of physical activity.” http://diabetes.niddk.nih.gov/DM/pubs/insulinresistance/ 5) Diabetes, IR, Severe Insulinopenia

  15. DeFronzo RA. Diabetes. 2009;58:773-795

  16. Path to Hyperglycemia and T2DM Hyperglycemia results from a combination of: • Pancreatic -cell dysfunction with impaired insulin secretion • Increased hepatic glucose production due to excessive glucagon • Decreased peripheral glucose uptake due to insulin resistance

  17. Type 2 Diabetes in Children (T2DM)-Rationale for Prevention • The pre-diabetic stage is definable and lengthy • Clear risk factors • Proven interventions successful in adults • T2DM is difficult to treat • Early complications are common at diagnosis, and likely to occur with time, leading to a huge healthcare burden • Insulin deficiency is progressive

  18. The Challenge of T2DM in Children • Prevalence of prediabetes and diabetes has increased significantly, despite obesity stabilization (NHANES 1999-2008*) • ½ of adolescents with T2DM fail metformin monotherapy, with rapid deterioration** This implies a more aggressive disease and a tendency toward more severe insulin deficiency *May et al. Pediatrics June 2012; 129(6): 1035-1041 **Today Study Group. NEJMJune 14, 2012; 366 (24): 2247-2256

  19. Does Treatment of Pre-diabetes Prevent T2DM? • No studies in children • Diabetes Prevention Program-3234 adults with Impaired Glucose Tolerance (NEJM 2002) • 58% reduction in T2DM with lifestyle • 31% reduction in metformin treated • In younger adults, reduction in T2DM in metformin group was similar to lifestyle

  20. Treatment of Adolescents at High Risk for T2DM • Lifestyle Change Remains the Cornerstone of Therapy: • Exercise: ideal 60 minutes of aerobic exercise daily for all children • Limit sedentary activites (TV, computers, video games) • Weight loss via calorie restriction. However, weight maintenance in a growing child = decrease in BMI • ?? some studies have suggested that a decrease in carbohydrate and/or focus on glycemic index may improve weight loss efforts

  21. Look AHEAD: Action for Health for Diabetes Intensive Lifestyle Intervention in Adult T2DM JAMA (2012) 308: 2489

  22. Treatment of Adolescents at High Risk for T2DM (medications) • Metformin (subsequent slides) • Others: no data in children for diabetes prevention

  23. The MOCA Trial (Metformin in Obese Children and Adolescents) • Prospective, randomized, double-blind, placebo-controlled trial of metformin in 151 obese children and adolescents with hyperinsulinemia and/or impaired fasting glucose or impaired glucose tolerance for 6 months • 67.5% females, 65.6% postpubertal, 23.8% Asian or Afro-Caribbean • age range 8–18 years (mean 13.7 (SD 2.3)) • mean BMI-SDS was 3.4 (SD 0.5). • Metformin dose: 1 g in the AM and 500 mg in the evening • Results: Metformin had a beneficial treatment effect over placebo for BMI-SDS (-0.1SD), fasting glucose (-0.16 mmol/l), ALT (-19%), with changes in BMI-SDS sustained at 6 months. J ClinEndocrinol Metab 98: 322–329, 2013

  24. Metformin for insulin resistance or pre-diabetes in children • Controversial • Off label • The benefit (extrapolated from adult studies) likely outweighs the risk in motivated patients. • General approach: • considermetformin (500 mg/day initial, max 1000 mg BID) in motivated patient after lifestyle intervention failure • Pre-diabetes (IFG or IGT) • Extreme high-risk group (PCOS or strong FHx DM in high-risk ethnic group) • Precautions: stop medicine with illness, hypoxia, CHF, dehydration (including contrast agents): theoretical risk of life threatening metabolic acidosis. Check renal function yearly, daily MVI

  25. diabetesmanager.pbworks.com

  26. B A • Bariatric surgery: • Laparoscopic adjustable gastric banding • Roux-en-Y gastric bypass • Sleeve gastrectomy: Horizontal (C) or vertical (D) resection of the stomach C D Arch PediatrAdolesc Med. 2012;166(8):757-766.

  27. Arch PediatrAdolesc Med. 2012;166(8):757-766.

  28. Who?Overweight child (BMI or wt/ht 85-94% ile), PLUS 2 risk factors: Family History of T2DM (1st or 2nd degree relative) Hispanic/ African American/ Am Indian, or Asian Pacific Islander Signs of insulin resistance (acanthosis, HTN, dyslipidemia, PCOS) Maternal history of diabetes or GDM during the child’s gestation When? At age 10 or younger if pubertal How often? Every 3 years How to screen? Fasting plasma glucose vs. HbA1c vs. Oral GTT. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care 2013 Jan; 36 (supplement 1): S14-15 Screening for T2DM in Children

  29. Back to our Patient: What to Do? • Labs: • Lipids: yes (universal screening at 9-11 years and 17-21 years-NHLBI Guidelines 2011) • Fasting chemistry profile: yes (glucose, LFT-Screen for non alcoholic fatty liver disease) • Consider Hemoglobin A1c, OGTT if the FBG is borderline • ? TFTs: not needed-normal growth, no symptoms or goiter • Treatment: • Diet and exercise intervention • Consider metformin if the FBG is abnormal and does not normalize with lifestyle intervention, or if OGTT/A1c are abnormal • Frequent (?) visits *PEDIATRICS Volume 120, Supplement 4, December 2007, S177.

  30. AAP: Clinical Practice Guideline Management of Newly Diagnosed Type 2 Diabetes Mellitus in Children and Adolescents • Key action statement 1: • Clinicians must ensure that insulin therapy is initiated for children and adolescents with T2DM who are ketotic or in DKA and in whom the distinction between T1DM and T2DM is unclear • And, insulin therapy should be initiated for patients with random BG >250mg/dL or HbA1c >9%

  31. AAP: Clinical Practice Guideline Management of Newly Diagnosed Type 2 Diabetes Mellitus in Children and Adolescents • Key action statement 2: • In all other instances, life style modifications should be initiated, including nutrition and physical activity. • Metformin should be used as first-line therapy at the time of diagnosis of T2DM. TODAY study: Metformin alone is not usually enough; Metformin + rosiglitazone is better but there are concerns regarding TZDs.

  32. AAP: Clinical Practice Guideline Management of Newly Diagnosed Type 2 Diabetes Mellitus in Children and Adolescents Key action statement 3: Clinicians should monitor HbA1c every 3 months and intensify treatment goals for BG and HbA1c (<7%) above target goals

  33. AAP: Clinical Practice Guideline Management of Newly Diagnosed Type 2 Diabetes Mellitus in Children and Adolescents • Key action statement 4: • Finger-stick BG should be monitored for patients who: • Are taking insulin or other hypoglycemic agents • Are initiating changes in DM treatment regimen • Have not met treatment goals • Have intercurrent illness

  34. AAP: Clinical Practice Guideline Management of Newly Diagnosed Type 2 Diabetes Mellitus in Children and Adolescents • Key action statement 5: • Importance of Nutrition counseling both at the time of diagnosis and as part of ongoing management • Balanced macronutrient diets for weight loss • Children aged 6-10y: 900-1200 kcal/day • Adolescents aged 13-18y: at least 1200 kcal/d

  35. AAP: Clinical Practice Guideline Management of Newly Diagnosed Type 2 Diabetes Mellitus in Children and Adolescents Key action statement 6: Importance of Daily Exercise: Children and adolescents with T2DM should engage in 60min of moderate exercise daily and limit screen time to <2hr/day.

  36. Beta Cell Mechanics

  37. SELECTED REFERENCES Barlow, SE, et al. Expert Committee Recommendations Regarding the Prevention, Assessment, and Treatment of Child and Adolescent Overweight and Obesity: Summary Report. Pediatrics 2007; 120:S164-S192. Bobo N, et al. An update on type 2 diabetes in youth from the National Diabetes Education Program. Pediatrics 2004 Jul;114(1):259-63. Kendall D, et al. Metformin in Obese Children and Adolescents: The MOCA Trial.J ClinEndocrinol Metab 98: 322– 329, 2013. Levy-MarchalC, Arslanian S, Cutfield W, Sinaiko A, DruetC, MarcovecchioML, Chiarelli F, on behalf of ESPE- LWPES-ISPADAPPES-APEG-SLEP-JSPE, and the Insulin Resistance in Children Consensus Conference Group 2010 Insulin resistance in children: consensus, perspective, and future directions. J ClinEndocrinol Metab 95:5189–5198. May AL, Kuklina EV, and Yoon PW. Prevalence of Cardiovascular Disease Risk Factors Among US Adolescents,1999-2008. Pediatrics June 2012; 129(6): 1035-1041 Monzavi R, et al. Improvement in risk factors for metabolic syndrome and insulin resistance in overweight youth who are treated with lifestyle intervention. Pediatrics 2006 June 117(6): e1111-e1118. Srinivasan S, et al. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J ClinEndocrinolMetab2006 June; 91:2074-2080. Ten S, Maclaren N. Insulin resistance syndrome in children. J ClinEndocrinol Metab 2004 Jun;89(6):2526-39. Today Study Group. A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes NEJMJune 14, 2012; 366 (24): 2247-2256 ,

  38. Insulin and glucagon dynamics pre- and post-meal

  39. Loss of Beta Cell Function through time

  40. Monogenic Diabetes Syndromes mrcpart1revision.blogspot.com Many of these genes are also involved in neonatal forms of diabetes mellitus

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